CN110545912A - Method for preparing deuterated ethanol from D2O - Google Patents

Method for preparing deuterated ethanol from D2O Download PDF

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CN110545912A
CN110545912A CN201880027170.5A CN201880027170A CN110545912A CN 110545912 A CN110545912 A CN 110545912A CN 201880027170 A CN201880027170 A CN 201880027170A CN 110545912 A CN110545912 A CN 110545912A
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ethanol
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劳伦特·莱福特
迈克·施密特坎普
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Deuteria Beverages LLC
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Abstract

The present invention relates to a process for the preparation of deuterated ethanol from ethanol, D2O, a ruthenium catalyst, and a co-solvent.

Description

Method for preparing deuterated ethanol from D2O
Technical Field
The present invention relates to a process for the preparation of deuterated alcohols from D2O.
background
Deuterium (D or 2H) is a stable, non-radioactive isotope of hydrogen. Deuterium-enriched organic compounds such as deuterated alcohols are known. U.S. patent No.8,658,236 describes an alcoholic beverage of water and ethanol in which at least 5 mole% of the ethanol is deuterated ethanol. It is believed that such alcoholic beverages may reduce the negative effects associated with drinking ethanol.
the production of alcoholic beverages containing deuterated ethanol requires the preparation of deuterated ethanol in an efficient, safe and cost-effective manner. Known methods of preparing deuterated alcohols (e.g., deuterated alcohols) involve H/D exchange reactions between non-deuterated alcohols and D2O. Depending on the method, the resulting deuterated alcohol can comprise deuterium at different positions. Examples of such methods are described in Chemistry Letters 34, No.2(2005), p.192-193 "Ruthenium catalyzed deuterium labelling of α -carbon in primary alcohol and primary/secondary amine in D2O"; adv. Synth. Catal.2008,350, p.2215-2218, "A method for the regioselective depletion of alcohols"; org.Lett.2015,17, p.4794-4797 "Ruthenium catalyst selected α -and α, β -Deutvation of alcohol use D2O" and Catalysis Communications 84(2016) found in "effective ingredients of alcohol in degraded water catalyst by Ruthenium catalyst compounds".
other routes to deuterated alcohols involve several sequential reactions that require expensive and/or hazardous materials. For each of these transformations, purification and isolation of intermediates is necessary.
in view of the above, it would be desirable to be able to synthesize deuterated alcohols in an efficient, safe, and cost-effective manner. It is further desirable to synthesize deuterated alcohols having deuteration only at the desired position or positions.
disclosure of Invention
in one aspect, the present invention provides a process for preparing deuterated ethanol from ethanol, D2O, a ruthenium catalyst, and a co-solvent.
These and other aspects, which have been achieved by the novel process for the preparation of deuterated alcohols discovered by the inventors, will become apparent in the following detailed description.
Detailed Description
it has now been surprisingly found that the combination of D2O, a ruthenium catalyst and a co-solvent allows for efficient and selective deuteration of ethanol.
Catalysis communications2016, 84, 67-70 (CC), mentions deuteration of alcohols by catalysis, but does not mention the use of co-solvents. Only for the deuteration of 1-butanol, not for the deuteration of ethanol. It has now been found that in the system described in CC where the catalyst is, ethanol is not deuterated when 1-butanol is replaced by ethanol.
CC also mentions the catalytic deuteration of ethanol using 20 mol% NaOH. It has now been found that in the system described in CC, where the catalyst is, deuteration of ethanol is not possible when NaOH is replaced by other bases. However, it was surprisingly found that the addition of a co-solvent to dissolve the catalyst results in an efficient deuteration of ethanol, especially in the absence of NaOH.
Accordingly, in one aspect, the present invention provides a novel process for the preparation of deuterated alcohols of formula (I):
CRRRCRROH (I)
The method comprises the following steps: reacting ethanol and D2O in the presence of a ruthenium catalyst of formula (II) and a co-solvent:
Wherein:
R1-R5 are independently H or D, provided that the abundance of D in R4 and R5 is at least 70%;
Each R6 is independently selected from: H. a C1-10 alkyl group, a substituted C1-10 alkyl group, a C6-18 aromatic ring group, and a substituted C6-18 aromatic ring group;
Each Ar is independently selected from a C6-18 aromatic ring group and a substituted C6-18 aromatic ring group;
Each n is independently 1 or 2;
L is a ligand;
An X counterion; and
the catalyst was soluble in a mixture of ethanol, D2O and a co-solvent.
In another aspect, the process is carried out in the absence of a base.
In another aspect, the method is performed in the absence of NaOH.
The abundance of D in R4 and R5(CH2 position) and in R1, R2 and R3(CH3 position) can be determined by 1H NMR. A 70% abundance of D in R4 and R5 means that 70% of all R4 and R5 present are D (as distinguished from a natural abundance of 0.01%).
In another aspect, the abundance of D in R4 and R5 is at least 80%. Other examples of abundances of D in R4 and R5 include at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 99.5%.
In another aspect, the introduction of D occurs preferentially in R4 and R5 rather than R1-R3. In another aspect, the abundance of D in R1-R3 is at most 50%. Other examples of abundances of D in R1-R3 include up to 45, 40, 35, 30, 25, 20, 15, 10, 5, and 1%.
In another aspect, the abundance of D in R4 and R5 is at least 90%, and the abundance of D in R1-R3 is at most 5%. Further examples include (a) at least 95% and at most 1%, and (b) at least 99% and at most 1%.
in the present method, the conversion of ethanol to deuterated ethanol can be determined by 1H NMR. The conversion is the molar ratio of deuterated ethanol formed divided by the initial amount of starting ethanol (unenriched ethanol). In one aspect, the percent conversion (molar ratio x 100) is at least 90%. Other examples of percent conversion include at least 95%, at least 98%, and at least 99%.
the co-solvent together with ethanol and D2O formed a mixture in which the catalyst was soluble. Examples of co-solvents include Tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether (MTBE), diisopropyl ether, 1,2 dimethoxyethane, toluene (tol), benzene, xylene, 1, 4-dioxane, diglyme (diethylene glycol diethyl ether), cyclopentyl methyl ether (CPME), ethyl acetate, 1, 2-dichloroethane, dimethylacetamide, dimethylformamide, and dimethylsulfoxide.
the co-solvent may also be deuterated, wherein one or more H atoms of the co-solvent are substituted with D. Examples of deuterated co-solvents include d 8-tetrahydrofuran, d 8-toluene, and d8-1, 4-dioxane.
The reaction mixture may be single-phase or biphasic. For example, in the case where the co-solvent is toluene or cyclopentyl methyl ether, the mixture is biphasic.
The amount of co-solvent is generally not too high in order to increase the loading of the reactor and thus the productivity. Thus, in another aspect, the volume ratio of D2O to co-solvent in the reaction step is greater than 0.5. Other examples of volume ratios include 1-30. Further examples of volume ratios include at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 to 30. The upper limit of the volume ratio is usually about 30.
in another aspect, the molar ratio of D2O to ethanol in the reacting step is at least 3. Other examples of molar ratios include 3-10, 3-75, and 3-100. Further examples of molar ratios include at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 to 30. This results in a higher D incorporation at the desired location. The upper limit of the molar ratio is usually 75 or 100.
Ruthenium catalysts of formula (II) are known (see US8,003,838, US2013/0303774 and US2016/0039853, which are incorporated herein by reference).
Ligand "L" is any ligand suitable for deuterium enrichment of ethanol according to the presently claimed invention. In another aspect, the ligand is selected from: monodentate ligands. Examples of monodentate ligands include phosphines (e.g., triphenylphosphine), carbon monoxide, olefins, water, acetonitrile, dimethylsulfoxide.
In another aspect, the ligand L is carbon monoxide (CO).
In another aspect, the counterion X is selected from: pentamethylcyclopentadienyl, chloride, bromide, iodide, hydride, triflate and BH 4.
In another aspect, one of the counterions X is hydrogen radical.
In formula (II), on the other hand, two vicinal R6 (excluding hydrogen atoms) may form a cyclic structure through a covalent bond of a carbon atom with or without passing through a nitrogen atom, an oxygen atom, or a sulfur atom.
In another aspect, in formula (II), each Ar is phenyl.
In another aspect, N is 1 (each P is bonded to N in the Ru complex through a 2 carbon linker).
In another aspect, N is 2 (each P is bonded to N in the Ru complex through a 3 carbon linker).
In another aspect, n is 1 and all R6 are hydrogen.
In another aspect, L is carbon monoxide and one of X is hydrogen radical.
In another aspect, the catalyst is a Ru complex of formula (III) (which is commercially available) ({ bis [2- (diphenylphosphino) ethyl ] amine } carbonyl ruthenium (II) hydrochloride)):
wherein Ph is phenyl.
In another aspect, the catalyst is a compound of formula (III) and the reaction is carried out in the presence of an alkali metal borohydride.
Examples of alkali metal borohydrides include LiBH4, NaBH4, and KBH 4.
In another aspect, the catalyst is a compound of formula (III) and the reaction is carried out in the presence of NaBH 4.
in another aspect, the catalyst is a compound of formula (III) and the reaction is carried out in the presence of an alkali metal borohydride and in the absence of NaOH.
in another aspect, the catalyst is a compound of formula (III) and the reaction is carried out in the presence of NaBH4 and in the absence of NaOH.
It was found that the use of a suitable co-solvent for compound (III) in combination with an alkali metal borohydride allows for a higher selectivity for the introduction of D in R4-R5 than in R1-R3.
In another aspect, the catalyst is a Ru complex of formula (IV) (which is commercially available) ((hydrogenated carbonyl (tetrahydroboron) [ bis (2-diphenylphosphinoethyl) amino ] ruthenium (II)):
Wherein Ph is phenyl.
in another aspect, the catalyst is a compound of formula (IV) and the reaction is carried out in the absence of a base.
It was found that the combination of the catalyst of formula IV and a suitable co-solvent can result in a higher selectivity for the introduction of D in R4-R5 than in R1-R3.
Deuterated ethanol (I) can be obtained by reacting the entire amount of D2O with ethanol in one step (as described above), or D2O in multiple steps with distillation steps in between the mixing steps (as described below). Thus, in another aspect, the reacting step comprises:
a. The first fraction D2O was reacted with ethanol,
b. Collecting the distillate from the reaction mixture, and
c. A second portion of D2O was added to the distillate, and the unreacted ethanol was further reacted with D2O.
in another aspect, after step c), the method further comprises: repeating steps b) and c) one or more times until the desired level of D incorporation is reached. Thus, in another aspect, the reacting step comprises:
a) Reacting a first portion of D2O with ethanol;
b) Collecting the distillate from the reaction mixture;
c) Adding a second portion of D2O to the distillate to further react with unreacted ethanol;
d) Collecting the distillate from the reaction mixture; and the number of the first and second groups,
e) A third portion of D2O was added to the distillate to further react with unreacted ethanol.
In another aspect, the reacting step comprises:
a) Reacting a first portion of D2O with ethanol;
b) Collecting the distillate from the reaction mixture;
c) Adding a second portion of D2O to the distillate to further react with unreacted ethanol;
d) Collecting the distillate from the reaction mixture;
e) A third portion of D2O was added to the distillate to further react with unreacted ethanol;
f) collecting the distillate from the reaction mixture; and
g) A fourth portion D2O was added to the distillate to further react with unreacted ethanol.
when multiple steps are used, the amount of D2O needed to achieve the desired D incorporation in ethanol is advantageously reduced compared to the case where the entire amount of D2O is mixed with ethanol in one step. In step a), the first fraction D2O was reacted with ethanol to obtain a partially reacted mixture with a certain degree of D incorporation in ethanol. The partially reacted mixture also included H2O formed as a by-product of D incorporation in ethanol, which inhibited further D incorporation in ethanol. In step b), the partially reacted mixture is distilled to collect a distillate comprising mainly deuterated and non-deuterated alcohols. The distillate included only a very small amount of H2O. A second portion of D2O was added to the distillate, which allowed further D introduction.
In another aspect, the molar ratio of D2O mixed with ethanol in the reaction step in each reaction sub-step (a/c, a/c/e/g, etc.) is selected from 1,2, 3, 4, and 5.
In another aspect, the reaction temperature is at most 200 ℃. Examples of reaction temperatures include from 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175 to 180 ℃. Other examples include 50-160 ℃. Other examples include from 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155 to 160 ℃.
in another aspect, the reaction is carried out over a period of 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 to 100 hours. Examples of reaction run times include 1,2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70 to 72 hours.
In another aspect, compound (I) may be isolated from the reaction product by any conventional work-up procedure for organic synthesis. In addition, the crude product can be purified to high purity by standard methods including activated carbon treatment, fractional distillation, recrystallization, and column chromatography, as desired. The solution after the reaction can be directly distilled and recovered conveniently.
in the case of conducting the reaction in the presence of a base, the target compound having a higher acidity easily forms a salt or a complex with the base used, and remains in the distillation residue during the distillation recovery operation. In this case, the target compound can be obtained in high yield by previously neutralizing the reaction-completed solution with an organic acid (e.g., formic acid, acetic acid, citric acid, oxalic acid, benzoic acid, methanesulfonic acid, or p-toluenesulfonic acid) or an inorganic acid (e.g., HCl, HBr, HNO3, H2SO4), and then subjecting the reaction-completed solution after neutralization to a distillation recovery operation (including recovery by washing the distillation residue with an organic solvent such as diisopropyl ether).
It is noted that the present invention relates to all possible combinations of features described herein. Thus, it should be recognized that all combinations of features associated with the compositions according to the present invention are described herein; all combinations of features relating to the method according to the invention; and all combinations of features relating to the composition according to the invention and features relating to the method according to the invention.
it is to be understood that the description of a product/composition comprising several components also discloses a product/composition consisting of these components. A product/composition consisting of these components may be advantageous in that it provides a simpler, more economical process for preparing the product/composition. Similarly, it should be understood that the description of a method comprising several steps also discloses a method consisting of these steps. A process consisting of these steps may be advantageous because it provides a simpler, more economical process.
definition of
Unless otherwise indicated, the examples provided in the definitions of the present application appear to be non-inclusive. They include but are not limited to the enumerated examples.
When referring to values for the lower and upper limits of a parameter, ranges formed by combinations of the lower and upper limits are also understood to be disclosed.
"alkyl" includes a specified number of carbon atoms in a straight chain, branched chain, and cyclic (when the alkyl group has 3 or more carbon atoms) configuration. Alkyl includes lower alkyl groups (C1, C2, C3, C4, C5 and C6 or 1-6 carbon atoms). Alkyl also includes higher alkyl groups (> C6 or 7 or more carbon atoms).
When a group ends with "ene", it indicates that the group is linked to two other groups. For example, methylene (methylene) refers to the moiety-CH 2-.
"alkenyl" includes a specified number of hydrocarbon atoms in a straight or branched chain configuration that may have one or more unsaturated carbon-carbon bonds at any stable point along the chain, such as ethenyl and propenyl; c2-6 alkenyl includes C2, C3, C4, C5 and C6 alkenyl groups.
"alkynyl" includes a specified number of hydrocarbon atoms in a straight or branched chain configuration which may have one or more carbon-carbon triple bonds at any stable point along the chain, such as ethynyl and propynyl. C2-6 alkynyl includes C2, C3, C4, C5 and C6 alkynyl groups.
"substituted alkyl" is an alkyl group in which one or more hydrogen atoms have been replaced by another chemical group (substituent). The substituents include: halogen, OH, OR (wherein R is a lower alkyl group), CF3, OCF3, NH2, NHR (wherein R is a lower alkyl group), NRxRy (wherein Rx and Ry are independently lower alkyl groups), CO2H, CO2R (wherein R is a lower alkyl group), C (O) NH2, C (O) NHR (wherein R is a lower alkyl group), C (O) NRxRy (wherein Rx and Ry are independently lower alkyl groups), CN, C2-6 alkenyl, C2-6 alkynyl, C6-12 aromatic ring group, substituted C6-12 aromatic ring group, 5-12 membered aromatic heterocyclic group, and substituted 5-12 membered aromatic heterocyclic group.
examples of the aromatic ring group are aromatic hydrocarbon groups represented by phenyl, naphthyl and anthracenyl.
Examples of aromatic heterocyclic groups are aromatic hydrocarbon groups containing a heteroatom (e.g., nitrogen, oxygen, or sulfur), represented by pyrrolyl (including nitrogen-protected forms), pyridyl, furyl, thienyl, indolyl (including nitrogen-protected forms), quinolyl, benzofuryl, and benzothienyl.
"substituted aromatic ring group" or "substituted aromatic heterocyclic group" refers to an aromatic ring group/aromatic heterocyclic group in which at least one hydrogen atom has been substituted with another chemical group. Examples of such other chemical groups include: halogen, OH, OCH3, CF3, OCF3, NH2, NHR (wherein R is a lower alkyl group), NRxRy (wherein Rx and Ry are independently lower alkyl groups), CO2H, CO2R (wherein R is a lower alkyl group), c (o) NH2, c (o) NHR (wherein R is a lower alkyl group), c (o) NRxRy (wherein Rx and Ry are independently lower alkyl groups), CN, lower alkyl, aryl and heteroaryl.
"halogen" means Cl, F, Br or I.
other features of the present invention will become apparent during the following description of exemplary embodiments thereof, which are given for the purpose of illustration and are not intended to limit the invention.
Examples
The structure of the catalyst (II) tested is as follows:
cy ═ cyclohexyl.
OTf ═ trifluoromethanesulfonic acid group (trifluoromethanesulfonic acid group).
the experiment was performed by placing the catalyst (and base if needed) in a 5mL vial under an N2 atmosphere. When used, a mixture of ethanol and D2O was added, followed by the addition of the co-solvent. The vial was capped and the temperature was raised to the desired reaction temperature while stirring with magnetic stirring at 500 rpm. After 16h, the reaction mixture was cooled. After purging with N2, the autoclave was opened and the reaction mixture was analyzed by 1HNMR to determine D incorporation.
the abundance of D in the CH2 position was determined by the amount of residual H in the CH2 position. The "residual H in CH2 position" was determined by the normalized ratio of the area of the CH2 signal in ethanol divided by the area of the CH3 signal in ethanol. The complement of 100 to this number is equal to the abundance of D in the CH2 position.
Reaction mixture: all reaction mixtures contained EtOH: D2O and the indicated co-solvent. The volume of the co-solvent was 1mL in all cases.
ratio 1 is the ratio of EtOH to D2O.
The ratio 2 is EtOH to millimolar ratio of catalyst.
DCM ═ dichloromethane.
NMP ═ N-methyl-2-pyrrolidone.
Experiment 1: when no co-solvent is used, no D incorporation occurs at the desired CH2 position.
experiments 2-6: when the co-solvents THF (tetrahydrofuran), toluene, CPME (cyclopentylmethyl ether), dioxane or diglyme were used, the catalyst was dissolved in a mixture of ethanol, D2O and the co-solvent, and D incorporation occurred at the desired CH2 position.
Experiments 7-11: when co-solvents DCM (dichloromethane), CH3CN, acetone, tBuOH or NMP (N-methyl-2-pyrrolidone) were used, little or no D incorporation occurred at the desired CH2 position.
These results do not depend on whether the co-solvent is deuterated or not.
Experiments 12-15: when no co-solvent was used, no D incorporation occurred at the desired CH2 position, regardless of the type of base or the presence of NaBH 4.
Experiment 16: when NaBH4 was not used, no D incorporation occurred at the desired CH2 position, regardless of the type of cosolvent.
Experiments 17-19: the combination of co-solvent and NaBH4 gave D incorporation at the desired CH2 position.
Experiments 20-27, 29 and 31-34: when no co-solvent is used, no or little D incorporation occurs at the desired CH2 position, regardless of the type of catalyst.
Experiments 28 and 30: when the catalyst is ru (h) (BH4) (dppp) (dpen) or Cp × ir (bipy) (otf)2, no D incorporation occurs at the desired CH2 position, even in the presence of a co-solvent.
experimental group 4
various types of catalysts were tested in the presence of non-deuterated toluene and THF. The results are shown in table 4.
TABLE 4
Reaction mixture: all reaction mixtures contained EtOH: D2O and the indicated co-solvent.
The ratio 2 is EtOH to millimolar ratio of catalyst.
EtOH: D2O ratio (mmol) ═ 4.1:37.9
Reaction volume 2mL (1mLD2O: EtOH, 1mL cosolvent)
experiments 35-36: the use of a non-deuterated co-solvent in combination with achieves D incorporation at the desired CH2 position.
Experiments 37-44: the use of co-solvents with other catalysts results in insufficient D incorporation at the desired CH2 position.
Experimental group 5
The effect of molar ratio of D2O: EtOH and amount of co-solvent on the degree of D incorporation was tested. The molar ratio of D2O to EtOH in the following experiments was 46 compared to about 5-20 in experimental group 1. The results are shown in table 5.
TABLE 5
Reaction mixture: all reaction mixtures contained EtOH: D2O and the indicated co-solvent.
The ratio 2 is EtOH to millimolar ratio of catalyst.
EtOH: D2O ratio (mmol): 1:46
Reaction volumes 1mLD2O EtOH + various volumes of toluene.
The high molar ratio of D2O: EtOH gave a very high D incorporation of 97%. All experiments achieved the same level of D incorporation even when only 12% (v/v) toluene was used. This may be advantageous for increasing the load on the reactor and thus increasing the productivity.
Many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims (20)

1. Method for preparing deuterated ethanol shown as formula (I)
CRRRCRROH (I)
The method comprises the following steps: reacting ethanol with D2O in the presence of a ruthenium catalyst of formula (II) and a co-solvent:
Wherein:
R1-R5 are independently H or D, provided that the abundance of D in R4 and R5 is at least 70%;
Each R6 is independently selected from: a hydrogen atom, a C1-10 alkyl group, a substituted C1-10 alkyl group, a C6-18 aromatic ring group, and a substituted C6-18 aromatic ring group;
each Ar is independently selected from a C6-18 aromatic ring group and a substituted C6-18 aromatic ring group;
Each n is independently selected from the integer 1 or 2;
L is a ligand;
X is a counterion;
the catalyst is soluble in a mixture of ethanol, D2O, and the co-solvent.
2. The method of claim 1, wherein the abundance of D in R4 and R5 is at least 80%.
3. The method of claim 1, wherein the abundance of D in R1-R3 is at most 50%.
4. The method of claim 1, wherein the abundance of D in R4 and R5 is at least 90%, and the abundance of D in R1-R3 is at most 5%.
5. the process of claim 1, wherein the catalyst is selected from the group consisting of catalysts of formulas III and IV:
6. The process of claim 5, wherein the catalyst is of formula (III).
7. The process of claim 5, wherein the catalyst is of formula (III) and the reaction is carried out in the presence of an alkali metal borohydride.
8. The method of claim 7, wherein the alkali metal borohydride is NaBH 4.
9. The process of claim 8, wherein the co-solvent is selected from tetrahydrofuran, toluene, 1, 4-dioxane, diglyme and cyclopentyl methyl ether.
10. the process of claim 5, wherein the catalyst is of formula (III) and the reaction is carried out in the presence of an alkali metal borohydride and in the absence of NaOH.
11. The method of claim 10, wherein the alkali metal borohydride is NaBH 4.
12. The process of claim 11, wherein the co-solvent is selected from tetrahydrofuran, toluene, 1, 4-dioxane, diglyme and cyclopentyl methyl ether.
13. The process of claim 5, wherein the catalyst is of formula (IV).
14. the process of claim 13, wherein the co-solvent is selected from tetrahydrofuran, toluene, 1, 4-dioxane, diglyme and cyclopentyl methyl ether.
15. the process of claim 5, wherein the catalyst is of formula (IV) and the reaction is carried out in the absence of a base.
16. The process of claim 15, wherein the co-solvent is selected from tetrahydrofuran, toluene, 1, 4-dioxane, diglyme and cyclopentyl methyl ether.
17. the method of claim 1, wherein the reacting step comprises:
a) Reacting a first portion of D2O with ethanol;
b) Collecting the distillate from the reaction mixture; and the number of the first and second groups,
c) A second portion of D2O was added to the distillate to further react the unreacted ethanol with D2O.
18. The process of claim 17, wherein the molar ratio of D2O to ethanol mixed in each of the reaction sub-steps a) and c) is independently 1-5.
19. The method of claim 1, wherein the reacting step comprises:
a) Reacting a first portion of D2O with ethanol;
b) Collecting the distillate from the reaction mixture;
c) Adding a second portion of D2O to the distillate to further react with unreacted ethanol;
d) Collecting the distillate from the reaction mixture; and the number of the first and second groups,
e) A third portion of D2O was added to the distillate to further react with unreacted ethanol.
20. the process of claim 19, wherein the molar ratio of D2O to ethanol mixed in each of the reaction sub-steps a), c), and e) is independently 1-5.
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